What are the key principles of preventing gram negative bacteria - Enterobacteriacea?

Enterobacteriaceae (e.g., E. coli, Klebsiella sp, Enterobacter sp, Citrobacter sp., Proteus sp., etc) include a large number of gram negative bacilli that are normal colonizers of the human gastrointestinal tract. Other reservoirs include water, plants, soil, and gastrointestinal tract of other animals. Enterobacteriaceae are the most commonly isolated bacteria from clinical specimens (combining inpatient and outpatient specimens) and comprise 21% of all nosocomial isolates in the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) surveillance system in 2006-2007. The two most common organisms, Escherichia coli and Klebsiella pneumoniae, account for 15% of all health care infections.

Specifically, this family accounts for 12.4% of catheter-line associated blood stream infections and 12% of all blood stream infections, 34% of all nosocomial urinary tract infections, 18% of surgical site infections, and 23% of ventilator-associated pneumonias.

There is increasing resistance of these enterobacteriaceae to antibiotics, with endemic rates of organisms resistant to quinolones; third and fourth generation cephalosporins due to endemicity of extended spectrum beta-lactamases (ESBLs) and plasmid mediated amp-C type enzymes; and more recently, the resistance to carbapenem antibiotics via the two most common mechanisms - Klebsiella Pneumoniae Carbapenemase (KPC), and New Delhi Metallobetalactamase-1 (NDM-1), which cause resistance to the broadest of all beta-lactam antibiotics. These carbapenem resistant organisms also contain multidrug resistant genetic elements that code for resistance to most other antibiotics.

Only few antimicrobial agents like colistin, tigecycline, and certain aminoglycosides have consistent in-vitro activity against these carbapenem resistant enterobacteriaceae (CRE), with rising reports of organisms resistant to all available antibiotics. CRE are associated with high morbidity and mortality, with few if any antibiotic treatment options currently and in the near future. CRE have demonstrated epidemic potential, spreading rapidly within individual healthcare settings, and across large geographical areas, and are now endemic across the East Coast United States, Israel, Greece, and India/Pakistan.

With few treatment options for patients infected with CRE, infection control to limit spread of these organisms is critical. However, the best methods to prevent spread are complex, and multi-faceted; and scientific data are still being generated. Nevertheless, the most important goal is early detection within a facility or region, and aggressive containment to limit spread of CRE while incidence is low.

The best infection control practices will include use of sensitive detection methods within the microbiology laboratory, rapid communication of the presence and importance of CRE organisms from microbiology to infection control, aggressive hand-washing, contact precautions and cohorting, antibiotic stewardship, monitoring of admissions of patients from high risk environments (nursing homes, long term care facilities, intensive care units, travel history), use of active surveillance to identify colonization, and communication between public health, and other health care facilities.

What are the conclusions of clinical trials and meta-analyses regarding control of gram negative bacteria - Enterobacteriacea?

The majority of studies are in the setting of a common source or person to person outbreak. As a result, the studies are usually retrospective in design; interventions to control enterobactericeae include multiple interventions simultaneously, making it difficult to assess the relative importance of one aspect of infection control over another.

However, key conclusions in an outbreak situation, in particular of CRE, include:

All acute care facilities to establish protocol, in conjuction with Clinical and Laboratory Standards Institute (CLSI) to detect and immediately alert infection control members if identification of enterobacteriaceae non-susceptible (intermediate or resistant) carbapenems

Ensure proper care of invasive monitoring equipment; remove all invasive devices as soon as feasible, and as aseptically as possible

Optimize environmental cleaning and room disinfection

Limit use of broad-spectrum antibiotics as part of an antibiotic stewardship program

Use of initial point prevalence survey (active surveillance cultures of rectum/perirectum) to look for carbapenem resistant or non-susceptible enterobactericeae (CRE) colonization in high risk units, or if cases of CRE are identified within a facility

Weekly point prevalence surveys until no new cases identified within facility

Monitor rates of multidrug resistant enterobactericeae imported from outside hospitals, nursing homes, or long term acute care hospitals in order to identify transfer patients who are at highest risk for colonization with these organisms

Communication and cooperation with other health care facilities and public health departments to notify admission and transfer of patients with carbapenem resistant enterobacteriaceae (CRE)

What are the consequences of ignoring infection control practices related to gram negative bacteria - Enterobacteriacea?

The consequences of ignoring infection control practices related to gram negative enterobacteriaceae are dire. Infections with multi-drug resistant enterobacteriaceae, in particular carbapenem resistant enterobacteriaceae (CRE), are associated with high case fatality rates, as high as 58.8% fatality rate for patients in the ICU and 70-80% fatality rate among patients with bacteremia .

In addition, the plasmid-mediated Klebsiella pneumoniae carbapenemase (KPC) gene has been documented to spread rapidly in an institution(s), from one strain to another, and from one species to another, and can spread across a large geographical region, partially due to the emergence and clonal expansion of a dominant strain of KPC-producing Klebsiella pneumoniae designated multi-locus sequence type 258 (ST 258). Among patients who survive infection or remain colonized but asymptomatic from KPC-producing enterobacteriaceae, these patients are likely vectors of dissemination of these organisms to other patients in health care facilities and community.

Therefore, as treatment options are extremely limited and mortality unacceptably high, prevention, early detection, and early aggressive control are crucial.

Summary of current controversies.

1. Topical application of chlorhexadine: Use of chlorhexadine (topical antiseptic) is now being frequently used in a variety of settings- for hand washing, preoperative skin preparation, oral wash for gingivitis, and for bathing of skin. Its use has been shown to decrease rates of blood stream infections by gram positive organisms, and decrease rates of ventilator associated pneumonia in patients who underwent cardiac surgery. Recent outbreak investigations have used chlorhexadine baths as a part of their multifaceted infection control practices. However, evidence as of yet does not support routine use of chlorhexadine baths or oral solution to decrease rates of infection due to enterobacteriaceae.

2. Selective decontamination of the digestive tract: by orally administering non-absorbable antimicrobial agents has as its aim to prevent or eliminate gut colonization with pathogenic gram negative bacteria, with the goal to decrease rates of infections and mortality. The largest randomized study in ventilated patients in the ICU did show statistically significant decreases in ventilator associated pneumonias and mortality, with transient declines in colonization with multidrug resistant enterobacteriaceae during the 6-month period. However, once the study had concluded, the same units demonstrated rapid rise in multidrug resistant gram negative bacteria. Other studies have showed that in areas of high prevalence of MRSA and VRE, selective decontamination increases rates of infection and colonization with gram positive organisms. Therefore, widespread use of selective decontamination cannot be justified at his time. However, it may have a role to help limit an outbreak due to multidrug resistant enterobacteriaceae, including CRE, though data remains limited.

What is the impact of gram negative bacteria - Enterobacteriacea infections and the need for control relative to infections at other sites or from other specific pathogens?

Enterobacteriaceae are the most frequently isolated group of bacteria when outpatient and inpatient clinical specimens are combined. The family also accounts for 21% of all pathogens isolated in 2006-2007 NHSN surveillance system, which has steadily declined from 42% in 1980-1982, primarily driven by decreased rates of E. coli.

Conversely, gram positive organisms, such as Staphylococci and enterococcal species, have become more predominant causes of nosocomial infection since the early 1980's.

However, despite the lower prevalence of nosocomial infections due to enterobacteriaceae, because of alarming rates of widespread antibiotic resistance, especially to the broadest antibiotics (carbapenems), infection control of these carbapenem resistant enterobacteriaceae (CRE) is of extreme importance. Case reports have been known to document outbreaks of enterobacteriaceae that are resistant to all known antibiotics (including aminoglycosides, colisitin, and tigecycline), raising true concerns for a new pre-antibiotic era.

Large tertiary care center, Israel, with institutional and nation-wide outbreak

1. Contact precautions of all KPC positive patients2. Prevalence of colonization or infection reported daily to hospital management and national coordinator3. KPC positive patients entered into national database4. Admission rectal surveillance cultures of patients in step-down units, and intensive care units5. Weekly rectal surveillance cultures of patients in same units as above6. In other departments, surveillance cultures from patients with epidemiologic links to patient with KPC

1. Contact isolation for all patients with ceftazidime or carbapenem resistant gram-negative bacillus2. Cohorting of KPC positive patients and detected nurses for KPC positive patients3. Enhanced environmental cleaning with quarternary ammonium compound4. Member of infection control service participated on joint medical and/or nursing rounds 5 days per week5. Weekly rectal swabs and upon admission to unit5. Increased number of alcohol hand gels to increase compliance to hand washing

Significantly decreased number of patients with carbapenem resistant K. pneumoniae during intervention period compared to pre-intervention period (3.7+/-1.6 vs. 9.7+/- 2.2; p<.001)

Controversies in detail.

See Table II and Table III for information about the use of topical chlorhexadine to prevent infection with enterobacteriaceae and selective decontamination of the digestive tract as infection control practice of enterobacteriaceae, respectively.

Table II.

Summary of studies using topical chlorhexadine to prevent enterobacteriaceae infections

Study

Setting

Description

Conclusions

Munoz-price 2010

Single center, long term acute care facility, outbreak of KPC

Use of infection control bundle, which included daily 2% chlorhexadine baths of skin

Implementation of bundle able to limit transmission of KPC at single center

Bleasdale, 2007

Single center, ICU, 2-arm, crossover clinical trial

Daily 2% chlorhexadine baths of skin with CHG (chlorhexadine gluconate) impregnated cloths of all patients in study unit; daily baths with soap and water for patients in control arm

Despite significant decrease in incidence of gram-positive bacterial isolates regardless of source in CHG arm, no difference was found in incidence of gram negative bacteria between 2 arms.

Oropharygneal rinse with 0.12% chlorhexadine gluconate solution and nasal ointment containing chlorhexadine; or oral rinse and nasal ointment with placebo; administered 4 times a day from time of hospitalization until nasogastric tube removed (usually day after surgery)

Despite significant decline in nosocomial infections, lower respiratory tract infections, bacteremias and deep surgical site infections, most of decrease in infections were due to decrease in gram positive organisms. Though p-value not calculated in paper, does not appear to have decrease in enterobacteriaceae causing nosocomial infections

Relative risk in preventing VAP was 0.74, 26% relative risk reduction in VAP with use of chlorhexadine, with greatest beneficial effect seen in trials limited to cardiac surgery patients. Overall, no statistical difference in mortality

Table III.

Selective decontamination of the digestive tract as infection control practice of enterobacteriaceae

Randomized study. Patients received gel containing amphotericin B, tobramycin and colisitin 2% (SDD arm), or placebo, applied to oral mucosa q6 hours, and solution containing same antibiotics (SDD arm), or placebo, by mouth or nasogastric tube. Cefotaxime x3 days given to all patients, including placebo

Surveillance cultures showed effective decontamination of patients in SDD arm, but incidence of infection not significant changed. Pts in placebo arm have significantly more infections due to Enterobacteriaceae. Both arms showed increase in colonization of the gut with enterococci, and methicillin resistant staph aureus colonization increased in SDD group. No effect on mortality or morbidity

After adjusting for covariates, odds ratio for death at day 28 in SOD and SDD groups, compared to standard care were 0.85 (95% CI 0.74-0.99) and 0.83 (95%CI 0.72-0.97), both statistically significant. Pts receiving SDD have lower incidence of ICU-acquired bacteremia with enterobacteriaceae than those receiving SOD. Pts receiving SDD had decreased rates of rectal and oropharyngeal colonization with enterobacteriaceae, and decreased rates of multidrug resistant enterobacteriacae during both the SDD and SOD periods

Oostdijk 2010

Follow-up study of the deSmet 2009 study (see above)

Monthly point prevalence surveys of rectal and respiratory samples in all 13 ICUs, comparing results from the intervention period to the pre and post-intervention periods

During the SDD and SOD intervention arms, gram negative bacilli(GNR) resistance to ceftazidime slowly rose in respiratory tract; after SDD intervention, rebound effect of rapid rise in GNR resistance to ceftazidime in the intestinal tract

Brun-Buisson 1989

Single center, ICU, tertiary care center in France; outbreak setting of intestinal colonization and infection with multiresistant enterobacteriacae (resistant to third generation cephalosporins and aminoglycosides)